Hydroxypyridines and processes of preparing the same



Patented Feb. 14, 1950 UNITED STATES PATENT OFFICE HY DROXYPYRIDINES AND PROCESSES F PREPARING THE SAME Dorothea Heyl Hoffman, Rahway, No.12, .assignor;

to Merck & 00., 1110., Rahway, N. 1., a corporation of New Jersey No Drawing. Original application July 9, 1947,

Serial No. 159,909. Divided and. this application November 2, 1948, Serial No. 58,023v

7 Claims.

This invention relates to novel chemical compounds and processes of preparing the same. More particularly; it is concerned with 2-methyl- 3,4-dihydroxy-S-hydroxymethylpyridine and esters thereof.

This application is a division of'my copending,

application Serial No. 759,909, filed July 9, 1947.

These novel chemical compounds possess vitamin Be activity and in small quantities give very deep colors varying from red to purple with ferric salts. inks, dyes or as a means of determining traces,

of ferric ion in solution. Colored chelates are also obtained with other metals, such as copper. These novel compounds are also capable of coupling with diazonium hydroxides from aniline; p-aminobenzoic acid, etc., to give red dyes.

The compounds forming the subject matter of the present invention may be represented graph.- ically-as follows:

wherein R represents hydrogen and p-toluene-- sulfonyl group and R represents hydrogen, phosphono, calcium phosphono and p-toluenesulfonyl substituents;

Ithas now been discovered in accordance with the present invention that compounds of the above formula wherein R and R are hydrogen, fully defined by the chemical name 2'-methy1- These colored compounds may be used as;

3,4-dihydroxy--hydroxymethylpyrldine, can be prepared by reacting 2-methyl-3-hydroxy-4- formyl-5-hydroxymethylpyridine with hydrogen peroxide in an aqueous alkaline medium.

Various esters of 2-methyl-3,4-dihydroxy-5- hydroxymethylpyridine such as the phosphate of the 5-hydroxymethyl, and p-toluenesulfonate, esters of the 3-hydroxy-5 hydroxymethyl groups have now been prepared. A process for prepar- 10 ing 2-methyl 3,4 dihydroxy 5 phosphonoxymethylpyridine involves reacting 2-methyl-3,4- dihydroxy-S-hydroxymethylpyridine successively with phosphorus oxyhalide and calcium carbonate in aqueous medium, recovering the calcium salt of 2-methyl-'3,4-dihydroxy-5-phosphonoxymethylpyridine and reacting the latter compound with hydrochloric acid to form 2-methyl-3,4-dihydroxy-5-phosphonoxymethylpyridine.

An alternative method for preparing Z-methyl- 3, 4,-dihydroxy-5-phosphonoxymethylpyridine involves reacting the calcium salt of 2-methyl-3- hydroxyi-formyl-5-phosphonoxymethylpyridine with sodium hydroxide and hydrogen peroxide.

The 2-methyl-3,4-dihydroxy-5-hydroxymethylpyridine can be converted to the p-toluenesulfonyl ester by reacting 2-methyl-3A-dihydroxy- S-hydroxymethylpyridine with p-toluene sulfonyl-chloride in a pyridine medium and recovering Z-methyl 3v p toluene-sulfonoxy-l-hydroxy-5-hydroxymethylpyridine and 2-methyl-3- P-rtOlUEHBSHlfODOXY 4 hydroxy-5-p-toluenesulfonoxymethylpyridine by fractional crystallization.

This process can be represented graphically as follows:

CHO

E0 CHiOPOlC B BIC NaOH

HO omoroin,

OHIOPOCB In carrying out the process ofthe present in vention, 2-methyl 3 hydroxy-4-formyl-d hydroxymethylpyridine hydrochloride is dissolved in water. The solution is cooled and adjusted to pH 10. The mixture containing the free base,

2-methyl-3-hydroxy 4-f0rmyl-5-hydroxymeth-' ylpyridine is then reacted with hydrogen peroxide. The mixture is cooled, acidified and 2methyl-3,4-dihydroxy-5-hydroxymethylpyri'dine crystals separate from solution.

These crystals are recovered and suspended in water. The aqueous solution is'treate'd first with phosphorus oxychloride and later with calcium The precipitate of the calcium salt carbonate. of 2-methyl-3,4-dihydroxy-5-phosphonoxymeth-; ylpyridine is recovered. 'The calcium salt is suspended in water, the solution adjusted to pH 2. and 2-methyl-3,4-dihydroxy 5 phosphonoxymethylpyridine crystals separate from solution.

The alternative process for preparing 2-1nethyl-3,4-dihydroxy-5 phosphonoxymethylpyridine involves reacting 2-methyl-3-hydroxy-4-formyl- 5-calcium phosphonoxymethylpyridine with sodiumhydroxide and hydrogen peroxide. I

The p-toluenesulfonyl esters can be. prepared by reacting 2methyl-3,4-dihydroxy-5-hydroxy methylpyridine with p-toluene sulfonylchloride in a pyridine medium. Cold water is added to the mixture which results in the formation of an oil. droxy-5-hydroxymethylpyridine crystallizes after other has been added to the mixture. Cooling of the aqueous mother liquor results in the crystallization of 2-methyl-3-p-toluenesulfonoxy-4-. hydroxy-5-p-toluenesulfonoxymethylpyridine.

The following examples illustrate a method of carrying out the present invention, but it is to be, understood that these examples are given by way of illustration and not of limitation.

Example 1 5.0 g. of 2-methyl-3 hydroxy-4-formyl-5-hydroxymethylpyridine hydrochloride was dissolved in cc. of water. The solution was cooled in an ice bath and sufficient 6 N sodium hydroxide was added to adjust the solution to pH 10. The bright yellow mixture thus formed was removed from the ice bath and hydrogen peroxide was added, several drops at a time. After about 5 cc. of the hydrogen peroxide had been added, the mixture became almost colorless. The mixture was then cooled in an ice bath and the solution acidified to pH 5 with hydrochloric acid. After further cooling, crystals of 2-methyl-3,4-dihydroxy-5-hydroxymethylpyridine separated from solution. The mixture was filtered and the crystals washed successively with water, alcohol and ether. The crystals had a melting point of 225.5- 226.5 C. with decomposition. Two recrystallizations from water did not change the melting point. This material gave a purple color with ferric chloride solution.

Analysis calculated for C7H9NO3:{ C, 54.16; H, 5.85; N, 9.03. Found: C, 54.40; H, 5.94; N, 8.97.

Example 2 Fifteen cubic centimeters of phosphorus oxychloride was added dropwise with mechanical stirring to 2.? g. of 2-methyl-3,4-dihydroxy-5- hydroxymethylpyridine suspended in 21 cc. of water. The rate of addition was regulated so that the temperature of the mixture did not rise above C. After an additional half hour of stirring and removal of excess hydrogen chloride under reduced pressure, the mixture was sur-- rounded by a water bath at 5 C. A suspension of calcium carbonate in water was added until the color turned pink, carbon dioxide was no longer evolved, and the solution was pH 5. After "an" hour of chilling, the precipitate was removed by filtration and washed with ice water. The aqueous solution, totaling 150 00., was diluted with three volumes of alcohol. After 2 hours of cooling, the pink precipitate of the calcium salt of 2-methyl -3,4- dihydroxy-5-phosphonoxymethylpyridine was centrifuged and washed twice with alcohol and once with ether.

The calcium salt described above was suspended in water, cooled in ice, and sufficient 6 N hydrochloric acid was added to adjust the solution to pH 2. The crystals of free 2-methyl-3,4- dihydroxy 5 phosphonoxymethylpyridine were filtered and washed successively with water, alcohol and ether. These crystals had a melting point of 229 C. which was not depressed when the material was mixed with a sample prepared by oxidation of codecarboxylase (2-methyl-3- hydroxy 4 formyl 5 phosphonoxymethylpyridine).

' Example 3 A saturated oxalic acid solution was added dropwise with thorough stirring to 100 mg. of the calcium salt of 2-methyl-3-hydroxy-4-formyl-5- phosphonoxymethylpyridine (estimated by assay to be about pure) until the yellow solid had all disappeared. The White precipitate 'of calcium oxalate was removed by centrifuging and Washed twice with water. The combined solution and washings were chilled in an ice bath and made alkaline (pH 10) by the dropwise addition of sodium hydroxide solution. Several drops of hydrogen peroxide (30%) was added, also dropwise, and the solution warmed to room temperature. The color change from bright yellow to a very pale yellow required about ten minutes.

After removal of some calcium hydroxide by centrifuging, the solution, chilled in ice, was acidified (pH 2) with N hydrochloric acid. The Z-methyl- 3,4 dihydroxy 5 phosphonoxymethylpyridine crystallized promptly from solution. The crystals were removed and washed successively with ice The crystals had a- Water, alcohol and ether. melting point of 229-230 C. with decomposition and gave a purple color with ferric chloride solution.

Analysis calculated for ClHmNOsP: C, 35.73; H, 4.29; N, 5.96; P. 13.19. Found, C, 35.55; H, 4.63; N, 5.73; P. 13.00.

Ernample 4 wellwashed successively with water, alcohol and ether.

The crude 2-methyl-3-p-toluenesulfonoxy-4-hydroxy-5-hydroxymethy1pyridine was recrystallized 3 times from alcohol, the final product melting at 228-229 C. with decomposition.

Analysis calculated for C14H15N05S: C, 54.36; H, 4.89; N, 4.53. Found: C, 54.66; H, 5.09; N, 4.70. The ether was sucked off the filtrate from which the crude material in the above prepare- 1 tion had been separated, and the aqueous solu- H, 4.59; N, 3.02; S, 13.83. Found: C, 54.53; H,

Modifications may be made in carrying out the present invention without departing from thespirit and scope thereof and the invention is to be limited only by the appended claims.

I claim:

1. The process that comprises reacting 2- methyl-3-hydroxy-4-formyl -5 hydroxymethyl pyridine with hydrogen peroxide in an aqueous alkaline medium, recovering the 2-methyl-3,4'- dihydroxy 5 hydroxymethylpyridine phorus oxyhalide and calcium carbonate in aqueous medium, recovering the calcium salt of-2- methyl 3,4 dihydroxy-5-phosphonoxymethylpyridine, reacting the latter compound with hydrochloric acid and recovering the 2-methyl-3,4- dihydroxy 5 phosphonoxymethylpyridine thus formed.

2. The process that comprises reacting 2- methyl 3-hydroxy-4-formyl-5-hydroxymethylpyridine with hydrogen peroxide in an aqueous alkaline medium, acidifying the latter mixture.

thusv formed, reacting the latter compound with phosrecovering the 2 methyl-3,4-dihydroxy-5-hydroxymethylpyridine thus formed, reacting the latter crystals with phosphorus oxychloride and calcium carbonate in an aqueous medium, recovering the calcium salt of 2-methyl-3,4-dihydroxy 5-phosphonoxymethylpyridine, reacting the latter compound with hydrochloric acid and recovering 2-methyl-3,4-dihydroxy 5 phosphonoxymethylpyridine.

3. The process that comprises reacting 2- methyl 3-hydroxy-4-formyl-5-hydroxymethylpyridine with hydrogen peroxide in an aqueous alkaline medium and recovering the Z-methyl- 3,4 dihydroxy 5 hydroxymethylpyridine thus formed.

4. The process that comprises reacting 2- methyl 3,4 dihydroxy 5 hydroxymethylpyridine with phosphorus oxyhalide and calcium carbonate in aqueous solution and recovering the calcium salt of 2smethyl-3,4-dihydroxy-5- phosphonoxymethylpyridine thus formed.

5. The process that comprises reacting the calcium salt of Z-methyl-3,4-dihydroxy-5-phosphonoxymethylpyridine with hydrochloric acid and recovering the 2- methyl-3,4-dihydroxy-5- phosphonoxymethylpyridine thus formed.

6. 2 methyl 3,4 dihydroxy-S-hydroxymethylpyridine.

7. Calcium salt of 2-methyl-3,4-dihydroxy-5- phosphonoxymethylpyridine.

DOROTHEA HEYL HOFFMAN.

No references cited. 

1. THE PROCESS THAT COMPRISES REACTING 2METHYL-3-HYDROXY-4-FORMYL-5-HYDROXYMETHYLPYRIDINE WITH HYDROGEN PEROXIDE IN AN AQUEOUS ALKALINE MEDIUM, RECOVERING THE 2-METHYL-3,4DIHYDROXY - 5 - HYDROXYMETHYLPYRIDINE THUS FORMED, REACTING THE LATTER COMPOUND WITH PHOSPHOROUS OXYHALIDE AND CALCIUM CARBONATE IN AQUEOUS MEDIUM, RECOVERING THE CALCIUM SALT OF 2METHYL - 3,4 - DIHYDROXY-5-PHOSPHONOXYMETHYLPYRIDINE, REACTING THE LATTER COMPOUND WITH HYDROCHLORIC ACID AND RECOVERING THE 2-METHYL-3,4DIHYDROXY-5-PHOSPHONOXYMETHYLPYRIDINE THUS FORMED.
 7. CALCIUM SALT OF 2-METHYL-3,4-DIHYDROXY-5PHOSPHONOXYMETHYLPRIDINE. 